Refining Management of Immune-Checkpoint Inhibitor Toxicities in Melanoma

The rapid evolution of immune checkpoint inhibitors (ICIs) has fundamentally changed the prognosis for patients with advanced melanoma and other cutaneous malignancies. However, these therapies are associated with a diverse spectrum of immune-related adverse events (irAEs) that can affect virtually any organ system. At the 22nd Annual International Symposium on Melanoma and Other Cutaneous Malignancies®, James Larkin, MD, PhD, professor and consultant medical oncologist at the Royal Marsden Hospital, detailed the complexities of managing these toxicities, emphasizing the need for personalized immunosuppression and vigilance for chronic or steroid-refractory cases.¹

1. The Spectrum of irAEs is Virtually Limitless

While common toxicities like rash or colitis are well-recognized, clinicians must remain vigilant for rare presentations. Larkin highlighted that irAEs can involve "almost anything," recently noting emerging cases of urethritis, cystitis, and autoimmune autonomic ganglionopathy. Possible mechanisms for underlying irAEs included T-cell infiltration, preexisting autoantibodies, or inflammatory cytokines.²

2. Differentiate Between Acute and Chronic Toxicities

Clinical management must account for the temporal patterns of toxicities.³

• Acute toxicities often peak early during treatment with anti–CTLA-4, anti–PD-1, or combination therapies.
• Chronic toxicities may persist for years following the cessation of ICI therapy and may even have a permanent impact on other immune processes.

3. Tailor Steroid Dosing to Organ-Specific Severity

Steroid management is not a "one size fits all" approach. Treatment should use the lowest effective dose for the shortest possible time.⁴

• No systemic steroids: Typically indicated for hypothyroidism or type 1 diabetes.
• Moderate dose (1 mg/kg): Often sufficient for hepatitis, colitis, or pneumonitis.
• PULSE (500 to 1000 mg): Reserved for life-threatening conditions such as myocarditis, severe myositis, or certain neurological toxicities.

4. Utilize Selective Immunosuppression for Steroid-Refractory Cases

When irAEs are refractory to corticosteroids, clinicians should transition to more selective agents based on the likely underlying mechanism.^4-6

• Tocilizumab (Actemra; anti–IL-6): Prescribed in cases of hepatitis, arthritis, pneumonitis, and nephritis.
• Infliximab (Remicade) or Adalimumab (Humira; anti–TNF-α): Targeted for colitis, gastritis, or arthritis.
• Rituximab (Rituxan; anti-CD20): Utilized for B-cell–mediated events like myasthenia gravis or ANCA-vasculitis.

“[Clinicians should] aim to tailor immunosuppression/modulation to the likely mechanism of toxicity in steroid-refractory cases,” Larkin noted.

5. Prioritize Correct Diagnosis and Multidisciplinary Care

Larkin concluded that accurate diagnosis is vital before escalating therapy. As demonstrated in the presented case study, a patient with suspected myocarditis based on a rapid drop of Troponin-I required collaboration with a cardio-oncology team. The patient was subsequently discharged with 70 mg of prednisolone. The patient was also being given ruxolitinib (Jakafi) in a 2x1 month course.At restaging, the patient showed a complete response to therapy with no further treatment given, and the patient has maintained a response.

References

1. Larkin J. Adverse events: managing ‘I-O’ toxicity. Presented at the 22nd Annual International Symposium on Melanoma and Other Cutaneous Malignancies; Beverly Hills, CA, February 21, 2026.
2. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158-168. doi:10.1056/NEJMra1703481
3. Johnson DB, Nebhan CA, Moslehi JJ, Balko JM. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol. 2022;19(4):254-267. doi:10.1038/s41571-022-00600-w
4. Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(12):1217-1238. doi:10.1016/j.annonc.2022.10.001
5. Haanen J, Ernstoff M, Wang Y, et al. Rechallenge patients with immune checkpoint inhibitors following severe immune-related adverse events: review of the literature and suggested prophylactic strategy. J Immunother Cancer. 2020;8(1):e000604. doi:10.1136/jitc-2020-000604
6. Martins F, Sykiotis GP, Maillard M, et al. New therapeutic perspectives to manage refractory immune checkpoint-related toxicities. Lancet Oncol. 2019;20(1):e54-e64. doi:10.1016/S1470-2045(18)30828-3.